title: Isoangustone A, a novel licorice compound, inhibits cell proliferation by targeting PI3K, MKK4, and MKK7 in human melanoma.
abstract: Licorice root is known to possess various bioactivities, including anti-inflammatory and anticancer effects. Glycyrrhizin, a triterpene compound, is the most abundant constituent of dried licorice root. However, high intake or long-term consumption of glycyrrhizin causes several side effects, such as hypertension, hypertensive encephalopathy, and hypokalemia. Therefore, finding additional active compounds other than glycyrrhizin in licorice that exhibit anticancer effects is worthwhile. We found that isoangustone A (IAA), a novel flavonoid from licorice root, suppressed proliferation of human melanoma cells. IAA significantly blocked cell-cycle progression at the G1-phase and inhibited the expression of G1-phase regulatory proteins, including cyclins D1 and E in the SK-MEL-28 human melanoma cell line. IAA suppressed the phosphorylation of Akt, GSK-3β, and JNK1/2. IAA also bound to phosphoinositide 3-kinase (PI3K), MKK4, and MKK7, strongly inhibiting their kinase activities in an ATP-competitive manner. Moreover, in a xenograft mouse model, IAA significantly decreased tumor growth, volume, and weight of SK-MEL-28 xenografts. Collectively, these results suggest that PI3K, MKK4, and MKK7 are the primary molecular targets of IAA in the suppression of cell proliferation. This insight into the biologic actions of IAA provides a molecular basis for the potential development of a new chemotherapeutic agent.
authors.affiliation: The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912. zgdong@hi.umn.edu.
authors.forename: Nu Ry
authors.initials: NR
authors.lastname: Song
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Madhusoodanan
authors.initials: M
authors.lastname: Mottamal
authors.forename: Jung Han Yoon
authors.initials: JH
authors.lastname: Park
authors.forename: Soon Sung
authors.initials: SS
authors.lastname: Lim
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D005434:Flow Cytometry; D006035:Glycyrrhiza / Q000737:chemistry*; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D007529:Isoflavones / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000893:Anti-Inflammatory Agents; D019695:Glycyrrhizic Acid; D007529:Isoflavones; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C551631:isoangustone A; C482559:MAP2K4 protein, human; C482569:MAP2K7 protein, human